title: Acylguanidines as bioisosteres of guanidines: NG-acylated imidazolylpropylguanidines, a new class of histamine H2 receptor agonists.
abstract: N1-Aryl(heteroaryl)alkyl-N2-[3-(1H-imidazol-4-yl)propyl]guanidines are potent histamine H2-receptor (H2R) agonists, but their applicability is compromised by the lack of oral bioavailability and CNS penetration. To improve pharmacokinetics, we introduced carbonyl instead of methylene adjacent to the guanidine moiety, decreasing the basicity of the novel H2R agonists by 4-5 orders of magnitude. Some acylguanidines with one phenyl ring were even more potent than their diaryl analogues. As demonstrated by HPLC-MS, the acylguanidines (bioisosteres of the alkylguanidines) were absorbed from the gut of mice and detected in brain. In GTPase assays using recombinant receptors, acylguanidines were more potent at the guinea pig than at the human H2R. At the hH1R and hH3R, the compounds were weak to moderate antagonists or partial agonists. Moreover, potent partial hH4R agonists were identified. Receptor subtype selectivity depends on the imidazolylpropylguanidine moiety (privileged structure), opening an avenue to distinct pharmacological tools including potent H4R agonists.
authors.affiliation: Departments of Pharmaceutical/Medicinal Chemistry, University of Regensburg, D-93053 Regensburg, Germany.
authors.forename: Prasanta
authors.initials: P
authors.lastname: Ghorai
authors.forename: Anja
authors.initials: A
authors.lastname: Kraus
authors.forename: Max
authors.initials: M
authors.lastname: Keller
authors.forename: Carsten
authors.initials: C
authors.lastname: Götte
authors.forename: Patrick
authors.initials: P
authors.lastname: Igel
authors.forename: Erich
authors.initials: E
authors.lastname: Schneider
authors.forename: David
authors.initials: D
authors.lastname: Schnell
authors.forename: Günther
authors.initials: G
authors.lastname: Bernhardt
authors.forename: Stefan
authors.initials: S
authors.lastname: Dove
authors.forename: Manfred
authors.initials: M
authors.lastname: Zabel
authors.forename: Sigurd
authors.initials: S
authors.lastname: Elz
authors.forename: Roland
authors.initials: R
authors.lastname: Seifert
authors.forename: Armin
authors.initials: A
authors.lastname: Buschauer
mesh_terms: D000215:Acylation; D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D017442:Histamine Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011970:Receptors, Histamine H2 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D006146:Guanidines; D017442:Histamine Agonists; D007093:Imidazoles; D011970:Receptors, Histamine H2